Feeds:
Posts
Comments

Archive for the ‘Drug Delivery Platform Technology’ Category


“Repurposing” Off-patent Drugs offers big hopes of New Treatments

Reporter: Irina Robu, PhD

 

Given the substantial costs and the slow pace of drug discovery and development, repurposing old drugs has become a practice, partly because it involves the use of already developed compounds. Yet, there is lack of clinical interest in repurposing off patent drugs.

However, the scale of the opportunity for drug repurposing is huge. Initially approved for one disease, these drugs went off-patent and now show potential in other diseases. Even so, many non-profit groups see promise in supporting trials into drug repurposing. There is a huge untapped medicine chest of generic drugs with unexploited uses. These generic drugs are often cheap, already approved, off-patent and relatively quick to develop, whereas new drugs can cost millions of dollars to develop, test and 45% of the drugs fail in clinical trials.

However, numerous non-profit groups see potential in supporting trials into drug repurposing. Epidemiological data can offer enticing leads. Yet, clinical trials for these drugs are costly, but the benefits can be huge. The Drugs for Neglected Diseases Initiative, a Swiss non-profit research group, supported research into fexinidazole, which was abandoned by a pharma at an early stage. The drug showed to have antiparasitic qualities. However, after years of work in January 2020, it was approved for sleeping sickness in the Democratic Republic of Congo. It is the first oral medicine for the disease, and works for all stages of it.

Up till now, when it comes to cancer the most promising generic pills are known. Cancer Research, a UK based charity is testing aspirin to see if can stop cancer from recurring; metformin in a large prostate-cancer trial; and an anti-fungal medication to treat bowel cancer. At the same time, the Anticancer Fund in Brussels hopes that propranolol in treating cancers of the inner lining of blood vessels and pancreatic cancer. Propranolol is a generic 1960s beta-blocker used for a wide range of ailments such as hypertension, anxiety and migraine. If approved for cancer, its cost would be negligible in comparison the tens of thousands of dollars a month usually charged for cancer medicines.

Money seems the crucial constraint with these drugs, in addition to the clinical trials needed to have these drugs updated and relabeled. Only the makers or original developers of a drug are permitted to adjust its label. Sanofi, based in Paris, was the firm that requested regulatory review of fexinidazole for sleeping sickness, while the research was a charitable effort. But drug firms are not forced to support non-commercial efforts to repurpose drugs. And outside the industry it is tough to find the legal expertise to be able to do the  necessary paperwork.

As non-profits make progress in repurposing, corporate interest may be rising. In terms of achieving new treatment options, this is good news. But it will not bring cheaper medicines in areas traditionally neglected by the drug industry. Firms will focus on finding ways to patent the new uses and charge high prices for the finished product.

If governments need cheaper drugs, non-profits will need financial incentives and a cooperative regulatory framework. They include making regulators give free advice and waive approval fees, and a public fund to support repurposing. Yet, when drugs are approved, investors are paid back by the public health service, which makes savings by using the newly approved generic drugs.

SOURCE

https://www.economist.com/international/2019/02/28/repurposing-off-patent-drugs-offers-big-hopes-of-new-treatments?fsrc=scn/tw/te/bl/ed/crosspurposesrepurposingoffpatentdrugsoffersbighopesofnewtreatmentsinternational

 

Other related articles published in this Online Scientific Open Access Journal include:

 

The Castleman Disease Research Network publishes Phase 1 Results of Drug Repurposing Database for COVID-19

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/06/27/the-castleman-disease-research-network-publishes-phase-1-results-of-drug-repurposing-database-for-covid-19/

Read Full Post »


Live Conference Coverage AACR 2020 in Real Time: Monday June 22, 2020 Late Day Sessions

 

Reporter: Stephen J. Williams, PhD

 

Follow Live in Real Time using

#AACR20

@pharma_BI

@AACR

 

Register for FREE at https://www.aacr.org/

 

AACR VIRTUAL ANNUAL MEETING II

 

June 22-24: Free Registration for AACR Members, the Cancer Community, and the Public
This virtual meeting will feature more than 120 sessions and 4,000 e-posters, including sessions on cancer health disparities and the impact of COVID-19 on clinical trials

 

This Virtual Meeting is Part II of the AACR Annual Meeting.  Part I was held online in April and was centered only on clinical findings.  This Part II of the virtual meeting will contain all the Sessions and Abstracts pertaining to basic and translational cancer research as well as clinical trial findings.

 

REGISTER NOW

 

 

 

Virtual Educational Session

Prevention Research, Science Policy, Epidemiology, Survivorship

Carcinogens at Home: Science and Pathways to Prevention

Chemicals known to cause cancer are used and released to the environment in large volumes, exposing people where they live, work, play, and go to school. The science establishing an important role for such exposures in the development of cancers continues to strengthen, yet cancer prevention researchers are largely unfamiliar with the data drawn upon in identifying carcinogens and making decisions about their use. Characterizing and reducing harmful exposures and accelerating the devel

Julia Brody, Kathryn Z. Guyton, Polly J. Hoppin, Bill Walsh, Mary H. Ward

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Tumor Biology, Molecular and Cellular Biology/Genetics, Clinical Research Excluding Trials

EMT Still Matters: Let’s Explore! – Dedicated to the Memory of Isaiah J. Fidler

During carcinoma progression, initially benign epithelial cells acquire the ability to invade locally and disseminate to distant tissues by activating epithelial-mesenchymal transition (EMT). EMT is a cellular process during which epithelial cells lose their epithelial features and acquire mesenchymal phenotypes and behavior. Growing evidence supports the notion that EMT programs during tumor progression are usually activated to various extents and often partial and reversible, thus pr

Jean-Paul Thiery, Heide L Ford, Jing Yang, Geert Berx

DETAILS

Monday, June 22

1:30 PM – 3:00 PM EDT

Virtual Educational Session

Tumor Biology, Experimental and Molecular Therapeutics, Molecular and Cellular Biology/Genetics

One of These Things Is Not Like the Other: The Many Faces of Senescence in Cancer

Cellular senescence is a stable cell growth arrest that is broadly recognized to act as a barrier against tumorigenesis. Senescent cells acquire a senescence-associated secretory phenotype (SASP), a transcriptional response involving the secretion of inflammatory cytokines, immune modulators, and proteases that can shape the tumor microenvironment. The SASP can initially stimulate tumor immune surveillance and reinforce growth arrest. However, if senescent cells are not removed by the

Clemens A Schmitt, Andrea Alimonti, René Bernards

DETAILS

Monday, June 22

1:30 PM – 3:00 PM EDT

Virtual Educational Session

Clinical Research Excluding Trials, Molecular and Cellular Biology/Genetics

Recent Advances in Applications of Cell-Free DNA

The focus of this educational session will be on recent developments in cell-free DNA (cfDNA) analysis that have the potential to impact the care of cancer patients. Tumors continually shed DNA into the circulation, where it can be detected as circulating tumor DNA (ctDNA). Analysis of ctDNA has become a routine part of care for a subset of patients with advanced malignancies. However, there are a number of exciting potential applications that have promising preliminary data but that h

Michael R Speicher, Maximilian Diehn, Aparna Parikh

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Methods Workshop

Clinical Research Excluding Trials, Clinical Trials, Experimental and Molecular Therapeutics, Molecular and Cellular Biology/Genetics

Translating Genetics and Genomics to the Clinic and Population

This session will describe how advances in understanding cancer genomes and in genetic testing technologies are being translated to the clinic. The speakers will illustrate the clinical impact of genomic discoveries for diagnostics and treatment of common tumor types in adults and in children. Cutting-edge technologies for characterization of patient and tumor genomes will be described. New insights into the importance of patient factors for cancer risk and outcome, including predispos

Heather L. Hampel, Gordana Raca, Jaclyn Biegel, Jeffrey M Trent

DETAILS

Monday, June 22

1:30 PM – 3:22 PM EDT

Virtual Educational Session

Regulatory Science and Policy, Drug Development, Epidemiology

Under-representation in Clinical Trials and the Implications for Drug Development

The U.S. Food and Drug Administration relies on data from clinical trials to determine whether medical products are safe and effective. Ideally, patients enrolled in those trials are representative of the population in which the product will be used if approved, including people of different ages, races, ethnic groups, and genders. Unfortunately, with few patients enrolling in clinical trials, many groups are not well-represented in clinical trials. This session will explore challenges

Ajay K. Nooka, Nicole J. Gormley, Kenneth C Anderson, Ruben A. Mesa, Daniel J. George, Yelak Biru, RADM Richardae Araojo, Lola A. Fashoyin-Aje

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Cancer Chemistry

Targeted Protein Degradation: Target Validation Tools and Therapeutic Opportunity

This educational session will cover the exciting emerging field of targeted protein degradation. Key learning topics will include: 1. an introduction to the technology and its relevance to oncology; 2. PROTACS, degraders, and CELMoDs; 3. enzymology and protein-protein interactions in targeted protein degraders; 4. examples of differentiated biology due to degradation vs. inhibition; 5. how to address questions of specificity; and 6. how the field is approaching challenges in optimizing therapies

George Burslem, Mary Matyskiela, Lyn H. Jones, Stewart L Fisher, Andrew J Phillips

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Bioinformatics and Systems Biology, Experimental and Molecular Therapeutics, Drug Development, Molecular and Cellular Biology/Genetics

Obstacles and opportunities for protein degradation drug discovery

Lyn H. Jones
  • PROTACs ubiquitin mediated by E3 ligases;  first discovered by DeShaies and targeted to specific proteins
  • PROTACs used in drug discovery against a host of types of targets including kinases and membrane receptors
  • PROTACs can be modular but lack molecular structural activity relationships
  • can use chemical probes for target validation
  • four requirements: candidate exposure at site of action (for example lipophilicity for candidates needed to cross membranes and accumulate in lysosomes), target engagement (ternary occupancy as measured by FRET), functional pharmacology, relevant phenotype
  • PROTACs hijack the proteosomal degradation system

Proteolysis-targeting chimeras as therapeutics and tools for biological discovery

George Burslem
  • first PROTAC developed to coopt the VHL ubiquitin ligase system which degrades HIF1alpha but now modified for EREalpha
  • in screen for potential PROTACS there were compounds which bound high affinity but no degradation so phenotypic screening very important
  • when look at molecular dynamics can see where PROTAC can add additional protein protein interaction, verifed by site directed mutagenesis
  • able to target bcr-Abl
  • he says this is a rapidly expanding field because of all the new E3 ligase targets being discovered

Expanding the horizons of cereblon modulators

Mary Matyskiela

Translating cellular targeted protein degradation to in vivo models using an enzymology framework

Stewart L Fisher
  • new targeting compounds have an E3 ligase binding domain, a target binding domain and a linker domain
  • in vivo these compounds are very effective; BRD4 degraders good invitro and in vivo with little effect on body weight
  • degraders are essential activators of E3 ligases as these degraders bring targets in close proximity so activates a catalytic cycle of a multistep process (has now high turnover number)
  • in enzymatic pathway the degraders make a productive complex so instead of a kcat think of measuring a kprod or productivity of degraders linked up an E3 ligase
  • the degraders are also affecting the rebound protein synthesis; so Emax never to zero and see a small rebound of protein synthesis

 

Data-Driven Approaches for Choosing Combinatorial Therapies

Drug combinations remain the gold standard for treating cancer, as they significantly outperform single agents. However, due to the enormous size of drug combination space, it is virtually impossible to interrogate all possible combinations. This session will discuss approaches to identify novel combinations using both experimental and computational approaches. Speakers will discuss i) approaches to drug screening in cell lines, the impact of the microenvironment, and attempts to more

Bence Szalai, James E Korkola, Lisa Tucker-Kellogg, Jeffrey W Tyner

DETAILS

Monday, June 22

3:45 PM – 5:21 PM EDT

Virtual Educational Session

Tumor Biology

Cancer Stem Cells and Therapeutic Resistance

Cancer stem cells are a subpopulation of cells with a high capacity for self-renewal, differentiation and resistance to therapy. In this session, we will define cancer stem cells, discuss cellular plasticity, interactions between cancer stem cells and the tumor microenvironment, and mechanisms that contribute to therapeutic resistance.

Robert S Kerbel, Dolores Hambardzumyan, Jennifer S. Yu

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Drug Development, Experimental and Molecular Therapeutics

Molecular Imaging in Cancer Research

This session will cover the fundamentals as well as the major advances made in the field of molecular imaging. Topics covered will include the basics for optical, nuclear, and ultrasound imaging; the pros and cons of each modality; and the recent translational advancements. Learning objectives include the fundamentals of each imaging modality, recent advances in the technology, the processes involved to translate an imaging agent from bench to bedside, and how molecular imaging can gui

Julie Sutcliffe, Summer L Gibbs, Mark D Pagel, Katherine W Ferrara

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Tumor Biology, Immunology, Experimental and Molecular Therapeutics, Drug Development

Tumor Endothelium: The Gatekeepers of Tumor Immune Surveillance

Tumor-associated endothelium is a gatekeeper that coordinates the entry and egress of innate and adaptive immune cells within the tumor microenvironment. This is achieved, in part, via the coordinated expression of chemokines and cell adhesion molecules on the endothelial cell surface that attract and retain circulating leukocytes. Crosstalk between adaptive immune cells and the tumor endothelium is therefore essential for tumor immune surveillance and the success of immune-based thera

Dai Fukumura, Maria M Steele, Wen Jiang, Andrew C Dudley

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Immunology, Experimental and Molecular Therapeutics

Novel Strategies in Cancer Immunotherapy: The Next Generation of Targets for Anticancer Immunotherapy

T-cell immunotherapy in the form of immune checkpoint blockade or cellular T-cell therapies has been tremendously successful in some types of cancer. This success has opened the door to consider what other modalities or types of immune cells can be harnessed for exert antitumor functions. In this session, experts in their respective fields will discuss topics including novel approaches in immunotherapy, including NK cells, macrophage, and viral oncotherapies.

Evanthia Galanis, Kerry S Campbell, Milan G Chheda, Jennifer L Guerriero

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Tumor Biology, Drug Development, Immunology, Clinical Research Excluding Trials

Benign Cells as Drivers of Cancer Progression: Fat and Beyond

Carcinomas develop metastases and resistance to therapy as a result of interaction with tumor microenvironment, composed of various nonmalignant cell types. Understanding the complexity and origins of tumor stromal cells is a prerequisite for development of effective treatments. The link between obesity and cancer progression has revealed the engagement of adipose stromal cells (ASC) and adipocytes from adjacent fat tissue. However, the molecular mechanisms through which they stimulate

Guojun Wu, Matteo Ligorio, Mikhail Kolonin, Maria T Diaz-Meco

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Clinical Research Excluding Trials, Experimental and Molecular Therapeutics, Tumor Biology

Dharma Master Jiantai Symposium on Lung Cancer: Know Thy Organ – Lessons Learned from Lung and Pancreatic Cancer Research

The term “cancer” encompasses hundreds of distinct disease entities involving almost every possible site in the human body. Effectively interrogating cancer, either in animals models or human specimens, requires a deep understanding of the involved organ. This includes both the normal cellular constituents of the affected tissue as well as unique aspects of tissue-specific tumorigenesis. It is critical to “Know Thy Organ” when studying cancer. This session will focus on two of the most

Trudy G Oliver, Hossein Borghaei, Laura Delong Wood, Howard C Crawford

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Methods Workshop

Clinical Trials

Clinical Trial Design: Part 1: Novel Approaches and Methods in Clinical Trial Design

Good clinical trial design has always had to balance the competing interests of effectively and convincingly answering the question with the limitations imposed by scarce resources, complex logistics, and risks and potential benefits to participants. New targeted therapies, immuno-oncology, and novel combination treatments add new challenges on top of the old ones. This session will introduce these concerns and 1) suggest ways to consider what outcomes are relevant, 2) how we can best

Mary W. Redman, Nolan A. Wages, Susan G Hilsenbeck, Karyn A. Goodman

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Methods Workshop

Tumor Biology, Drug Development

High-Throughput Screens for Drivers of Progression and Resistance

The sequencing of human cancers now provides a landscape of the genetic alterations that occur in human cancer, and increasingly knowledge of somatic genetic alterations is becoming part of the evaluation of cancer patients. In some cases, this information leads directly to the selection of particular therapeutic approaches; however, we still lack the ability to decipher the significance of genetic alterations in many cancers. This session will focus on recent developments that permit the identification of molecular targets in specific cancers. This information, coupled with genomic characterization of cancer, will facilitate the development of new therapeutic agents and provide a path to implement precision cancer medicine to all patients.

William C Hahn, Mark A Dawson, Mariella Filbin, Michael Bassik

DETAILS

Monday, June 22

3:45 PM – 5:15 PM EDT

Defining a cancer dependency map

William C Hahn

Introduction

William C Hahn

Genome-scale CRISPR screens in 3D spheroids identify cancer vulnerabilities

Michael Bassik

Utilizing single-cell RNAseq and CRISPR screens to target cancer stem cells in pediatric brain tumors

Mariella Filbin
  • many gliomas are defined by discreet mutational spectra that also discriminates based on age and site as well (for example many cortical tumors have mainly V600E Braf mutations while thalamus will be FGFR1
  • they did single cell RNAseq on needle biopsy from 7 gliomas which gave about 3500 high quality single cells; obtained full length RNA
  • tumors clustered mainly where the patient it came from but had stromal cell contamination probably so did a deconvolution?  Copy number variation showed which were tumor cells and did principle component analysis
  • it seems they used a human glioma model as training set
  • identified a stem cell like glioma cell so concentrated on the genes altered in these for translational studies
  • developed multiple PDX models from patients
  • PDX transcriptome closest to patient transcriptome but organoid grown in serum free very close while organoids grown in serum very distinct transcriptome
  • developed a CRISPR barcoded library to determine genes for survival genes
  • pulled out BMI1  and EZH2 (polycomb complex proteins) as good targets

Virtual Methods Workshop

Prevention Research, Survivorship, Clinical Research Excluding Trials, Epidemiology

Implementation Science Methods for Cancer Prevention and Control in Diverse Populations: Integration of Implementation Science Methods in Care Settings

Through this Education Session we will use examples from ongoing research to provide an overview of implementation science approaches to cancer prevention and control research. We draw on examples to highlight study design approaches, research methods, and real-world solutions when applying implementation science to achieve health equity. Approaches to defining change in the care setting and measuring sustained changes are also emphasized. Using real examples of patient navigation prog

Graham A Colditz, Sanja Percac-Lima, Nathalie Huguet

DETAILS

Monday, June 22

3:45 PM – 5:30 PM EDT

Virtual Educational Session

Regulatory Science and Policy, Epidemiology

COVID-19 and Cancer: Guidance for Clinical Trial Conduct and Considerations for RWE

This session will consider the use of real-world evidence in the context of oncology clinical trials affected by the COVID-19 pandemic. Key aspects of the FDA’s recent “Guidance on Conduct of Clinical Trials of Medical Products of Medical Products during COVID-19 Public Health Emergency” will be discussed, including telemedicine, accounting for missing data, obtaining laboratory tests and images locally, using remote informed consent procedures, and additional considerations for contin

Wendy Rubinstein, Paul G. Kluetz, Amy P. Abernethy, Jonathan Hirsch, C.K. Wang

 

 

Read Full Post »


Updates on the Oxford, AstraZeneca COVID-19 Vaccine

Reporter: Stephen J. Williams, PhD

AstraZeneca’s CEO states that their COVID-19 vaccine, codeveloped with Oxford University, should provide protection for a year.

AstraZeneca’s potential coronavirus vaccine is likely to provide protection against contracting Covid-19 for about a year, the company’s chief executive told a Belgian radio station on Tuesday.

The British drugmaker has already begun human trials of the vaccine developed by the University of Oxford, with a phase I trial in Britain due to end soon and a phase III trial already begun, Pascal Soriot told broadcaster Bel RTL.

“We think that it will protect for about a year,” Soriot said.

AstraZeneca said on Saturday that it had signed contracts with France, Germany, Italy and the Netherlands to supply the European Union with up to 400 million doses of the potential vaccine.

It has also agreed deals with Britain and the United States.

“If all goes well, we will have the results of the clinical trials in August/September. We are manufacturing in parallel. We will be ready to deliver from October if all goes well,” Soriot said.

Source: https://www.cnbc.com/2020/06/16/astrazeneca-covid-19-vaccine-likely-to-protect-for-a-year-ceo-says.html

 

 

From In The Pipeline (Derek Lowe’s regular column in Science)

Criticism of the Oxford Coronavirus Vaccine

By Derek Lowe 18 May, 2020

This piece at Forbes by Bill Haseltine has set off a lot of comment – it’s a look at the Oxford group’s vaccine candidate as compared to the SinoVac candidate, and you may recall (background here) that these are the two teams that have separately reported that their vaccines appear to protect rhesus monkeys from infection after exposure to the coronavirus. Haseltine has some criticisms of the Oxford data, and as you will see from that link to his name, his opinions deserve to be taken seriously. So what’s going on? Update: here’s the take on this at BioCentury.

Looking at the preprint on the Oxford results, Haseltine has a problem with the claim that the monkeys were protected from infection by a dose of ChAdOx1 nCoV-19. The key data are in the preprint’s Figure 3. The Oxford team checked for viral RNA several different ways. One was using bronchoaveolar lavage (BAL fluid), a sampling technique that involves running a bronchoscope down into the lungs and washing out aveolar spaces – a pretty darn invasive assay, which is why you don’t hear about it all that much compared to the still-not-so-nonivasive nose swabs. BAL fluid of the virus-exposed unvaccinated animals showed coronavirus genomic RNA throughout the study, and viral subgenomic RNA (more indicative of active replication) at days 3 and 5 after exposure. Meanwhile, the vaccinated animals showed the genomic RNA in only two monkeys, and no subgenomic RNA at all.

So far, so good. But both vaccinated and unvaccinated monkeys showed the same amount of viral genomic RNA from nose swab samples (Figure 3c). That’s the test that’s used out in the human population, and that means that the vaccinated animals would still be declared as positive for the coronavirus after being exposed to it. And the other thing that Haseltine notes is that the amount (the “titer”, in the lingo) of neutralizing antibodies in the blood of the vaccinated animals does not appear to be that high. You’d like to be able to dilute the blood antibody samples down by hundreds of times or even a thousandfold and still see antiviral activity in an in vitro assay, but in the Oxford case the activity started disappearing at about fortyfold dilution (Figure 2b).

On the positive side, 2/3 of the unvaccinated animals showed clear evidence of viral pneumonia at autopsy, but none of the vaccinated ones did. The conclusion is that the vaccinated animals were indeed infected – the vaccine did not protect against that – but that the disease was definitely less severe. But these results mean that the virus might well still be transmissible from people who had been so vaccinated, even if the disease course itself was not as deadly. You’d want to do better than that, if you can. Haseltine’s take is “Time will tell if this is the best approach. I wouldn’t bet on it.

Haseltine compares these results to the SinoVac inactivated virus vaccine, and finds that that one looks better – at its highest dose, no viral RNA was recovered from the tissues of the vaccinated animals, for example. This sort of “sterilizing immunity” is what you’d want to aim for – it gives the virus nowhere to go in the human population if you can vaccinate enough people. But it’s worth noting that the SinoVac results were from three doses of their vaccine (versus one of the Oxford candidate), and the viral exposure challenge was about half as strong (total viral particles) as what the Oxford paper used. The Oxford group also inoculated their monkeys in both the upper and lower respiratory tract, while the SinoVac team used a single inoculation in the trachea. So I agree with that tweet linked from AndyBiotech; I don’t think that a head-to-head comparison is fair. But Haseltine’s point stands, that the results as we have them from the ChAdOx1 nCoV-19 vaccine did not actually protect monkeys from infection.

Source: https://blogs.sciencemag.org/pipeline/archives/2020/05/18/criticism-of-the-oxford-coronavirus-vaccine

 

Please see other Articles on COVID-19 on our Coronavirus Portal Including Late Breaking News at:

https://pharmaceuticalintelligence.com/coronavirus-portal/

 

Read Full Post »


Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Opening Remarks and Clinical Session 11:45am-1:15pm Advances in Cancer Drug Discovery

SESSION VMS.CH01.01 – Advances in Cancer Drug Design and Discovery

April 27, 2020, 11:45 AM – 1:15 PM
Virtual Meeting: All Session Times Are U.S. EDT
DESCRIPTIONAll session times are U.S. Eastern Daylight Time (EDT).

Session Type
Virtual Minisymposium
Track(s)
Cancer Chemistry
14 Presentations
11:45 AM – 11:45 AM
– ChairpersonZoran Rankovic. St. Jude Children’s Research Hospital, Memphis, TN

11:45 AM – 11:45 AM
– ChairpersonChristopher G. Nasveschuk. C4 Therapeutics, Watertown, MA

11:45 AM – 11:50 AM
– IntroductionZoran Rankovic. St. Jude Children’s Research Hospital, Memphis, TN

11:50 AM – 12:00 PM
1036 – Discovery of a highly potent, efficacious and orally active small-molecule inhibitor of embryonic ectoderm development (EED)Changwei Wang, Rohan Kalyan Rej, Jianfeng Lu, Mi Wang, Kaitlin P. Harvey, Chao-Yie Yang, Ester Fernandez-Salas, Jeanne Stuckey, Elyse Petrunak, Caroline Foster, Yunlong Zhou, Rubin Zhou, Guozhi Tang, Jianyong Chen, Shaomeng Wang. Rogel Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, MI, Ascentage Pharma Group, Taizhou, Jiangsu, China

12:00 PM – 12:05 PM
– Discussion

12:05 PM – 12:15 PM
1037 – Orally available small molecule CD73 inhibitor reverses immunosuppression through blocking of adenosine productionXiaohui Du, Brian Blank, Brenda Chan, Xi Chen, Yuping Chen, Frank Duong, Lori Friedman, Tom Huang, Melissa R. Junttila, Wayne Kong, Todd Metzger, Jared Moore, Daqing Sun, Jessica Sun, Dena Sutimantanapi, Natalie Yuen, Tatiana Zavorotinskaya. ORIC Pharmaceuticals, South San Francisco, CA, ORIC Pharmaceuticals, South San Francisco, CA, ORIC Pharmaceuticals, South San Francisco, CA, ORIC Pharmaceuticals, South San Francisco, CA

12:15 PM – 12:20 PM
– Discussion

12:20 PM – 12:30 PM
1038 – A potent and selective PARP14 inhibitor decreases pro-tumor macrophage function and elicits inflammatory responses in tumor explantsLaurie Schenkel, Jennifer Molina, Kerren Swinger, Ryan Abo, Danielle Blackwell, Anne Cheung, William Church, Kristy Kuplast-Barr, Alvin Lu, Elena Minissale, Mario Niepel, Melissa Vasbinder, Tim Wigle, Victoria Richon, Heike Keilhack, Kevin Kuntz. Ribon Therapeutics, Cambridge, MA

12:30 PM – 12:35 PM
– Discussion

12:35 PM – 12:45 PM
1039 – Fragment-based drug discovery to identify small molecule allosteric inhibitors of SHP2. Philip J. Day, Valerio Berdini, Juan Castro, Gianni Chessari, Thomas G. Davies, James E. H. Day, Satoshi Fukaya, Chris Hamlett, Keisha Hearn, Steve Hiscock, Rhian Holvey, Satoru Ito, Yasuo Kodama, Kenichi Matsuo, Yoko Nakatsuru, Nick Palmer, Amanda Price, Tadashi Shimamura, Jeffrey D. St. Denis, Nicola G. Wallis, Glyn Williams, Christopher N. Johnson. Astex Pharmaceuticals, Inc., Cambridge, United Kingdom, Taiho Pharmaceutical Co., Ltd, Tsukuba, Japan

Abstract: The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signalling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Recent advances have shown that genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signalling and inhibits proliferation of RTK-driven cancer cell lines. SHP2 is now understood to act upstream of RAS and plays a role in KRAS-driven cancers, an area of research which is rapidly growing. Considering that RTK deregulation often leads to a wide range of cancers and the newly appreciated role of SHP2 in KRAS-driven cancers, SHP2 inhibitors are therefore a promising therapeutic approach.
SHP2 contains two N-terminal tandem SH2 domains (N-SH2, C-SH2), a catalytic phosphatase domain and a C-terminal tail. SHP2 switches between “open” active and “closed” inactive forms due to autoinhibitory interactions between the N-SH2 domain and the phosphatase domain. Historically, phosphatases were deemed undruggable as there had been no advancements with active site inhibitors. We hypothesised that fragment screening would be highly applicable and amenable to this target to enable alternative means of inhibition through identification of allosteric binding sites. Here we describe the first reported fragment screen against SHP2.
Using our fragment-based PyramidTM approach, screening was carried out on two constructs of SHP2; a closed autoinhibited C-terminal truncated form (phosphatase and both SH2 domains), as well as the phosphatase-only domain. A combination of screening methods such as X-ray crystallography and NMR were employed to identify fragment hits at multiple sites on SHP2, including the tunnel-like allosteric site reported by Chen et al, 2016. Initial fragment hits had affinities for SHP2 in the range of 1mM as measured by ITC. Binding of these hits was improved using structure-guided design to generate compounds which inhibit SHP2 phosphatase activity and are promising starting points for further optimization.

  • anti estrogen receptor therapy: ER degraders is one class
  • AZ9833 enhances degradation of ER alpha
  • worked in preclinical mouse model (however very specific)
  • PK parameters were good for orally available in rodents;  also in vitro and in vivo correlation correlated in rats but not in dogs so they were not sure if good to go in humans
  • they were below Km in rats but already at saturated in dogs, dogs were high clearance
  • predicted human bioavailability at 40%

 

12:45 PM – 12:50 PM
– Discussion

12:50 PM – 1:00 PM
1042 – Preclinical pharmacokinetic and metabolic characterization of the next generation oral SERD AZD9833Eric T. Gangl, Roshini Markandu, Pradeep Sharma, Andy Sykes, Petar Pop-Damkov, Pablo Morentin Gutierrez, James S. Scott, Dermot F. McGinnity, Adrian J. Fretland, Teresa Klinowska. AstraZeneca, Waltham, MA

1:00 PM – 1:05 PM
– Discussion

1:05 PM – 1:15 PM
– Closing RemarksChristopher G. Nasveschuk. MA

Follow on Twitter at:

@pharma_BI

@AACR

@GenomeInstitute

@CureCancerNow

@UCLAJCCC

#AACR20

#AACR2020

#curecancernow

#pharmanews

Read Full Post »


Self-propelled Liposomes as a Drug Delivery System

Reporter: Irina Robu, PhD

Liposomes are small artificial vesicles of spherical shape that can be created from cholesterol and natural non-toxic phospholipids. As a result of their size and hydrophobic and hydrophilic character, liposomes are promising systems for drug delivery. Liposome properties diverge considerably with lipid composition, surface charge, size, and the method of preparation. Scientists at Penn State developed self-propelled liposomes that migrate away and/or towards chemical signals, making it possible for self-directed drug delivery vehicles that can actively target a specific area of the body. Besides, the choice of bilayer components controls the ‘rigidity’ or ‘fluidity’ and the charge of the bilayer. Countless liposomes proposed for drug delivery are tissue-specific, since of antibodies on their surface bind to the target tissue when they encounter it. The technology may help to enhance efficacy and reduce side-effects of drugs in a variation of applications.

Yet, the key to drug delivery is enhancing the specificity and affinity of a drug delivery vehicle for its target tissue. As the drawbacks of conventional drug therapies, scientists are developing an extensive variability of drug delivery vehicles including nanoparticles, biomaterials, and implantable devices, to increase drug accumulation at a target site in the body and reduce side-effects elsewhere. To address the drawbacks, these researchers developed a type of liposome that can actively propel itself near a chemical signal in the body, such as a chemical attractant released by a target tissue.

The liposomes proposed by Penn researchers are covered in enzymes that react with specific substrates to produce energy, which can help to push the liposomes along, through a phenomenon called chemotaxis. By changing the enzymes coating the liposomes, the investigators can tune this chemotaxis and permit the particles to either move towards or away the chemical signal. This could aid the particles to gravitate near certain tissues, and possibly avoid others in the body.
Currently, the are still developing the liposomes, and hope that they will be able to use them for drug delivery soon
SOURCE
https://www.sciencedaily.com/releases/2019/11/191118110928.htm

Read Full Post »


Medicine in 2045 – Perspectives by World Thought Leaders in the Life Sciences & Medicine

Reporter: Aviva Lev-Ari, PhD, RN

 

This report is based on an article in Nature Medicine | VOL 25 | December 2019 | 1800–1809 | http://www.nature.com/naturemedicine

Looking forward 25 years: the future of medicine.

Nat Med 25, 1804–1807 (2019) doi:10.1038/s41591-019-0693-y

 

Aviv Regev, PhD

Core member and chair of the faculty, Broad Institute of MIT and Harvard; director, Klarman Cell Observatory, Broad Institute of MIT and Harvard; professor of biology, MIT; investigator, Howard Hughes Medical Institute; founding co-chair, Human Cell Atlas.

  • millions of genome variants, tens of thousands of disease-associated genes, thousands of cell types and an almost unimaginable number of ways they can combine, we had to approximate a best starting point—choose one target, guess the cell, simplify the experiment.
  • In 2020, advances in polygenic risk scores, in understanding the cell and modules of action of genes through genome-wide association studies (GWAS), and in predicting the impact of combinations of interventions.
  • we need algorithms to make better computational predictions of experiments we have never performed in the lab or in clinical trials.
  • Human Cell Atlas and the International Common Disease Alliance—and in new experimental platforms: data platforms and algorithms. But we also need a broader ecosystem of partnerships in medicine that engages interaction between clinical experts and mathematicians, computer scientists and engineers

Feng Zhang, PhD

investigator, Howard Hughes Medical Institute; core member, Broad Institute of MIT and Harvard; James and Patricia Poitras Professor of Neuroscience, McGovern Institute for Brain Research, MIT.

  • fundamental shift in medicine away from treating symptoms of disease and toward treating disease at its genetic roots.
  • Gene therapy with clinical feasibility, improved delivery methods and the development of robust molecular technologies for gene editing in human cells, affordable genome sequencing has accelerated our ability to identify the genetic causes of disease.
  • 1,000 clinical trials testing gene therapies are ongoing, and the pace of clinical development is likely to accelerate.
  • refine molecular technologies for gene editing, to push our understanding of gene function in health and disease forward, and to engage with all members of society

Elizabeth Jaffee, PhD

Dana and Albert “Cubby” Broccoli Professor of Oncology, Johns Hopkins School of Medicine; deputy director, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

  • a single blood test could inform individuals of the diseases they are at risk of (diabetes, cancer, heart disease, etc.) and that safe interventions will be available.
  • developing cancer vaccines. Vaccines targeting the causative agents of cervical and hepatocellular cancers have already proven to be effective. With these technologies and the wealth of data that will become available as precision medicine becomes more routine, new discoveries identifying the earliest genetic and inflammatory changes occurring within a cell as it transitions into a pre-cancer can be expected. With these discoveries, the opportunities to develop vaccine approaches preventing cancers development will grow.

Jeremy Farrar, OBE FRCP FRS FMedSci

Director, Wellcome Trust.

  • shape how the culture of research will develop over the next 25 years, a culture that cares more about what is achieved than how it is achieved.
  • building a creative, inclusive and open research culture will unleash greater discoveries with greater impact.

John Nkengasong, PhD

Director, Africa Centres for Disease Control and Prevention.

  • To meet its health challenges by 2050, the continent will have to be innovative in order to leapfrog toward solutions in public health.
  • Precision medicine will need to take center stage in a new public health order— whereby a more precise and targeted approach to screening, diagnosis, treatment and, potentially, cure is based on each patient’s unique genetic and biologic make-up.

Eric Topol, MD

Executive vice-president, Scripps Research Institute; founder and director, Scripps Research Translational Institute.

  • In 2045, a planetary health infrastructure based on deep, longitudinal, multimodal human data, ideally collected from and accessible to as many as possible of the 9+ billion people projected to then inhabit the Earth.
  • enhanced capabilities to perform functions that are not feasible now.
  • AI machines’ ability to ingest and process biomedical text at scale—such as the corpus of the up-to-date medical literature—will be used routinely by physicians and patients.
  • the concept of a learning health system will be redefined by AI.

Linda Partridge, PhD

Professor, Max Planck Institute for Biology of Ageing.

  • Geroprotective drugs, which target the underlying molecular mechanisms of ageing, are coming over the scientific and clinical horizons, and may help to prevent the most intractable age-related disease, dementia.

Trevor Mundel, MD

President of Global Health, Bill & Melinda Gates Foundation.

  • finding new ways to share clinical data that are as open as possible and as closed as necessary.
  • moving beyond drug donations toward a new era of corporate social responsibility that encourages biotechnology and pharmaceutical companies to offer their best minds and their most promising platforms.
  • working with governments and multilateral organizations much earlier in the product life cycle to finance the introduction of new interventions and to ensure the sustainable development of the health systems that will deliver them.
  • deliver on the promise of global health equity.

Josep Tabernero, MD, PhD

Vall d’Hebron Institute of Oncology (VHIO); president, European Society for Medical Oncology (2018–2019).

  • genomic-driven analysis will continue to broaden the impact of personalized medicine in healthcare globally.
  • Precision medicine will continue to deliver its new paradigm in cancer care and reach more patients.
  • Immunotherapy will deliver on its promise to dismantle cancer’s armory across tumor types.
  • AI will help guide the development of individually matched
  • genetic patient screenings
  • the promise of liquid biopsy policing of disease?

Pardis Sabeti, PhD

Professor, Harvard University & Harvard T.H. Chan School of Public Health and Broad Institute of MIT and Harvard; investigator, Howard Hughes Medical Institute.

  • the development and integration of tools into an early-warning system embedded into healthcare systems around the world could revolutionize infectious disease detection and response.
  • But this will only happen with a commitment from the global community.

Els Toreele, PhD

Executive director, Médecins Sans Frontières Access Campaign

  • we need a paradigm shift such that medicines are no longer lucrative market commodities but are global public health goods—available to all those who need them.
  • This will require members of the scientific community to go beyond their role as researchers and actively engage in R&D policy reform mandating health research in the public interest and ensuring that the results of their work benefit many more people.
  • The global research community can lead the way toward public-interest driven health innovation, by undertaking collaborative open science and piloting not-for-profit R&D strategies that positively impact people’s lives globally.

Read Full Post »


Injectable inclisiran (siRNA) as 3rd anti-PCSK9 behind mAbs Repatha and Praluent

 

Reporter: Aviva Lev-Ari, PhD, RN

Next stop, filing for approval. The Medicines Company has said it plans to submit inclisiran for FDA review by the end of 2019 and EMA review in the first quarter of 2020. If the drug’s approved it’ll be the third anti-PCSK9 behind mAbs Repatha and Praluent, and could try to compete on price to gain market share.

The company’s been very careful not to disclose its pricing plans for inclisiran, said ORION-10 principal investigator Dr. Scott Wright, professor and cardiologist at the Mayo Clinic. But, Wright said, The Medicines Co. and other companies he advises on clinical trial design “have learned the lesson from the sponsors of the monoclonal antibodies [against PCSK9], they’re not going to come in and price a drug that’s out of proportion to what the market will bear.” 

Because the anti-PCSK9 mAbs were initially priced beyond what patients and insurers were willing to pay, “now most of the physicians that I meet have a resistance to using them just because they’re fearful about the pre-approval process” with insurers, said Wright. “They’re much easier to get approved and paid for today than they’ve ever been, but that message is not out in the medical community yet.”

SOURCE

From: “STAT: AHA in 30 Seconds” <newsletter@statnews.com>

Reply-To: “STAT: AHA in 30 Seconds” <newsletter@statnews.com>

Date: Monday, November 18, 2019 at 2:59 PM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Interim look at Amarin data, an inclisiran update, & Philly’s giant heart

Read Full Post »


Advancing Drug Development – 12/12/2019, 8:30AM – 8:30PM at The University of Massachusetts Club, One Beacon Street, Boston, MA

 

Reporter: Aviva Lev-Ari, PhD, RN

4th Advancing Drug Development Forum – Making the Impossible Possible – Harnessing Small Molecule Drug Development scheduled to take place December 12th, 2019 at The University of Massachusetts Club, in Boston, Massachusetts from 8:30 AM – 8:30 PM.

http://advdrug.com/agenda/

 

Scientists are more than just chipping away and kicking down the barricades to develop complex small molecule products better and faster.  Successful companies are spending quality time finding novel and clever approaches and powerful technologies to better support their knowledgeable teams.  Often it takes establishing strong partnerships with 1 or more specialized service providers, cleverly combining resources – always striving to raise the bar in order to make life threatening diseases more of a chronic and tolerable disease or eradicated completely.

Hear from key opinion leaders in pharma, biotech, the investment community and innovative service providers on how they are meeting the challenges. Keep in mind, it takes being open-minded, flexible and willing sometimes to redesigning a new formulation that better enhances bioavailability, optimizes drug-delivery profiles, reduces dosing frequency, or improves the patient experience to have the potential to deliver quicker returns on investments than developing a completely new drug.

PROGRAM AGENDA Thursday, December 12, 2019
8:30 AM Registration and Networking Continental Breakfast
9:00 AM Welcome Address and Opening Remarks
Kevin Bittorf, Ph.D., & Shelly Amster
9:15 AM Opening VC Keynote
9:45 AM Bridging the Gap between Experimentation and Implementation
Panel Discussion
10:15 AM Refreshment Break
10:45 AM Cross-Talk Between Clin-Ops and Tech-Ops
Panel Discussion
11:15 AM The Cost of Speed and Value in Drug Development
Panel Discussion
12:00 PM Networking Luncheon
1:00 PM Advances in the Delivery of Therapeutics to the Brain
Academic Keynote
Mansoor M. Amiji, Ph.D., University Distinguished Professor, Professor of Pharmaceutical Sciences & Professor of Chemical Engineering, Northeastern University
1:30 PM Advancing Drug Delivery and Controlled Release
Panel Discussion
2:00 PM Drowning in DATA
2:30 PM Disruptive AI Technologies Improving Drug Development
3:00 PM Refreshment Break
3:30 PM Small Specialty VS Full Service – What Makes Sense for US?
Panel Discussion
4:00 PM Fireside Chat
Michael Bonney, Executive Chair, Kaleido Biosciences
Heinrich Schlieker, Ph.D., SVP Technical Operations, Sage Therapeutics
5:00 PM – 8:00 PM Networking Social
Direct electronic communication with Shelly Amster

Read Full Post »


Real Time Coverage @BIOConvention #BIO2019: Gene Therapy 2.0: No Longer Science Fiction 1:00-2:15 pm June 3 Philadelphia PA

Reporter: Stephen J. Williams Ph.D. @StephenJWillia2

kkjk

Other Articles on Gene Therapy on this Open Access Journal Include:

Read Full Post »


eProceedings – Day 1: Charles River Laboratories – 3rd World Congress, Delivering Therapies to the Clinic Faster, September 23 – 24, 2019, 25 Edwin H. Land Boulevard, Cambridge, MA

 

https://events.criver.com/event/9eab0ee1-982e-42c6-a4cd-fb43f9f2f1d0/confirmation:7c68cf9b-c599-469e-b602-42178c77e4f9

 

ANNOUNCEMENT

 

Leaders in Pharmaceutical Business Intelligence (LPBI) Group will cover this event in Real Time for pharmaceuticalintelligence.com 

Confirmation Number: 8ZNCBYNGHCK

In attendance generating in realtime event’s eProceeding and social media coverage by

 

Aviva Lev-Ari, PhD, RN

Director & Founder

Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston

Editor-in-Chief

http://pharmaceuticalintelligence.com 

e-Mail: avivalev-ari@alum.berkeley.edu

(M) 617-775-0451

https://cal.berkeley.edu/AvivaLev-Ari,PhD,RN

SkypeID: HarpPlayer83          LinkedIn Profile        Twitter Profile

#crlworldcon

@CRiverLabs

@pharma_BI

@AVIVA1950

 

 

Join us this year as we explore novel approaches to drug development that effectively reduce program timelines and accelerate delivery to the clinic. Using a variety of case studies, our speakers will illustrate methods that successfully cut time to market and highlight how artificial intelligence and genomics are expediting target discovery and drug development. In an agenda that includes presentations, panel discussions, and short technology demonstrations, you will learn how the latest science and regulatory strategies are helping us get drugs to patients faster than ever.

AGENDA

Day One, September 23, 2019

  • Novel approaches to silence disease drivers
  • The role of AI in expediting drug discovery

Monday, September 23

8:30 – 9:00 a.m. Introduction and Welcome Remarks James C. Foster, Chairman of the Board, President, and Chief Executive Officer, Charles River
9:00 – 9:30 a.m. 2019 Award Winner: A Silicon Valley Approach to Understanding and Treating Disease Matt Wilsey, Chairman, President, and Co-Founder, Grace Science Foundation
9:30 – 10:15 a.m. Keynote Session Brian Hubbard, PhD, Chief Executive Officer, Dogma Therapeutics
10:15 – 10:30 a.m. Break
10:30 – 11:15 a.m. Novel Approaches to Silence Disease Drivers Systemic Delivery of Investigational RNAi Therapeutics: Safety Considerations and Clinical Outcomes Peter Smith, PhD, Senior Vice President, Early Development, Alnylam Pharmaceuticals
11:15 a.m. – 12:00 p.m. Novel Approaches to Silence Disease Drivers: Considerations for Viral Vector Manufacturing to Support Product Commercialization Richard Snyder, PhD, Chief Scientific Officer and Founder, Brammer Bio
12:00 – 1:00 p.m. Lunch
1:00 – 1:45 p.m. Accelerating Drug Discovery Through the Power of Microscopy Images Anne E. Carpenter, Ph.D., Institute Scientist, Sr. Director, Imaging Platform, Merkin Institute Fellow, Broad Institute of Harvard and MIT
1:45 – 2:30 p.m. The Role of AI in Expediting Drug Discovery Target Identification for Nonalcoholic Steatohepatitis Using Machine Learning: The Case for nference Tyler Wagner PhD, Head of Cardiovascular Research, nference
2:30 – 2:45 p.m. Break
2:45 – 3:30 p.m. Technobite Sessions with Emulate Bio and University of Pittsburgh Drug Discovery Institute

Kyung Jin H Jang, VP of Bio Product development, Emulate, Inc.

Albert Gough, PhD, U Pittsburg School of Medicine

3:30 – 4:15 p.m. Artificial Intelligence Panel Discussion: Real World Applications from Discovery to Clinic Moderated by Carey Goldberg, WBUR
4:15 – 4:45 p.m. Jack’s Journey Jake and Elizabeth Burke, Cure NF with Jack
4:45 – 5:00 p.m. Closing Remarks
5:00 – 6:00 p.m. Networking Reception

 

 

Day Two – September 24, 2019

  • How genomics is expediting drug discovery
  • Accelerating therapies through the regulatory process

Tuesday, September 24

8:45 – 9:00 a.m. Opening Remarks and Recap James C. Foster, Chairman of the Board, President, and Chief Executive Officer, Charles River
9:00 – 9:30 a.m. 2018 Award Winner Update David Hysong, Patient Founder and Chief Executive Officer, Shepherd Therapeutics William Siders, CDO, Shepherd Therapeutics
9:30 – 10:15 a.m. Advances in Human Genetics and Therapeutic Modalities Enable Novel Therapies Eric Green, Vice President of Research and Development, Maze Therapeutics
10:15 – 11:00 a.m. How Genomics is Expediting Drug Discovery Manuel Rivas, Assistant Professor, Department of Biomedical Data Science, Stanford University
11:00 – 11:15 a.m. Break
11:15 a.m. – 12:00 p.m. Genomics Panel Discussion: Signposting Targets That Will Speed the Path to Market Moderated by Martin Mackay, Co-Founder, RallyBio
12:00 – 1:00 p.m. Lunch
1:00 – 1:45 p.m Truly Personalized Medicines for Ultra-rare Diseases: New Opportunities in Genomic Medicine Timothy Yu, Attending Physician, Division of Genetics and Genomics and Assistant Professor in Pediatrics, Boston Children’s Hospital
1:45 – 2:30 p.m. Application of Machine Learning Technology for the Assessment of Bulbar Symptoms in ALS Fernando Vieira, Chief Scientific Officer, ALS Therapy Development Institute
2:30 – 2:45 p.m. Break
2:45 – 3:30 p.m. Accelerating Rare Disease Therapies Through the Regulatory Process Martine Zimmermann, Senior Vice President and Head of Global Regulatory Affairs, Alexion Pharmaceuticals, Inc.
3:30 – 4:00 p.m. Wearing ALL the Hats: From Impossible to Possible Allyson Berent, Chief Operating Officer, GeneTx Biotherapeutics
4:00 – 4:15 p.m. Closing Remarks

 

jim.jpg
Matt_Wilsey.jpg
  • Find a cause and work with passion
  • CVD increased 53% from 2005 to 2016
  • Cholesterol, LDL receptor and CV disease
  • Genetics  evolution and discovery of PCSK9
  1. A PCSK9 Variant lowers CV risk
  2. complete lack of PCSK9 is safe – protects from CVD
  • LDL receptor
  • Statins do not work on LDL receptor if the mutation exists
  • Antibody and antisense for the PCSK9 mutation – Inexpensive Oral Medications can change Global Diseases
  • Dogma of Drug DIscovery: Approach a Patent vs Approach a Disease
  • Ligands bind within a cryptic binding pocket adjacent to a novel PCSK9 polymorphism

12 years of drug discovery

  1. 2003: PCSK9 mutation discovered
  2. 2005:
  3. 2006:
  4. 2012;
  5. 2012: Dogma Scientists begin
  6. compound found binds to primates
  7. 2015:
  8. 2018: Efficiency DGM-4403 lowers LDL-c by 55% 0ver 14 days
peter smith.jpg
  • 2014 – @Moderna, mRNA
  • 2017 – Alnylam

RNAi – delivery is the most difficult

  • gene silencing changes medicine and diseases
  • Small Interfeering RNA (siRNA) Therapeutics
  • Delivery challenges – stability and targeting
  • RNA Interference (RNAi) – Onpattro (patisiran)
  • GalNAc-siRNA Conjugates – delivery to the hepatocytes
  • N-Acetyl Galactosamine (GalNACc-siRNA conjugates
  • Hepatocyte specific : Liver across species: ASGPR expression
  • Metabolic Stability: Chemistry to Improve siRNA
  • Platform for genetic diseases
  • Evolution of COnjugate Design: GalNAc-siRNA – enhanced stabilization chemistry
  • ALN-TTRSC02 compared to Revusiran
  • ALN-TTRsc02 (advanced) –  – tetrameric protein binds transports serum retinol binding
  • AL Amyloidosis
  • ApoA1 Amyloidosis
  • ATTR Amyloidosis – manufacture in the Liver: Hereditery vs non-hereditary – Wild-Type
  • Patisiran Therapeutic Hypothesis – siRNA targeting TTR formulated
  • Pharmacology of TTR siRNA in Animal Model
  • V30M TTR Transgenic Mouse Model: Patisiran Phase 1 Study to Phase 3 APOLLA Study Design for any TTR mutation – Prior tetramer stabilizer used permitted
  • hATTR Amyloidosis and APOLLO Assessment: Phase 3 is Global – Cardiomyopathy – potential,
  • Patisiran met all secondary Endpoints: Canadian, Japanese approval – US approved indication, European approved
  • Alnylam Investigational RNAi Therapeutics:
  • Pipeline: Genetic medicines
  • Hepatic Infectious diseases
  • CNS & Ocular
  • Cardiovascular
11:15 AM-12:00 PM
richard snyder.jpg
  • Viral-Vector-mediated in vivo Gene Therapy
  • VVS Viral Vector Platforms:
  1. Adenovirus immunogenicity
  2. Lentivirus
  3. Retrovirus
  4. Herpes
  5. Recombinant Adeno-Associated Viral Vectors: Glybera, Luxturna
  6. Zolgenzma
  • Establish the product specifications based on data (CQAs)
  • Is the vector product: parenteral or anciliary material

Considerations:

  • Large scall vs small
  • lot demand vs platform choice
  • Proof of concept
  • Own/License the manufacturing reagents (portability) vs reliance on providers
  • Process and Analytical Design & Development: Cell line: Mamalian, others
  • Raw materials: Viral clearance steps – cell banks generation
  • impurity profiles
  • Cell Substrates
  • Cell clone screening
  • Preclinical/Clinical, Alachua, FL; Phase III/Commercial: Cambridge & Lexington
  • Biologics Upstream Process Flow: Master cell banks
  • Transient Transfection Process (Lenti and AAV)
  • rAAV Proviral cell line
  • Production Vector-based Process (Baculo or HSV)
  • Product purification: Filtration methods, Chromatography, centrifugal separation: Concentration/filtration
  • Formulation
  • Compatibility wiht vial: Glass, CZ, COP: absorption vs Inactivation
  • Single use
  • Frozen storage
  • Storage, Packing and Distribution
  • Technology Transfer: Research vs Mature Process (Qualified cell bank)
  • Plasmids: E.coli MCB backbone
  • Analytics Design & Development: Testing: Nucleic-acid based, protein-based
  1. AAV Vector Lot Release Assays
  2. Lentivirus
  • QA: QA Management System –
  • Analytical Assays
  • FDA Issues SIX New Draft Guidance Documents in 7/2018
  • Process Validation: Life cycle approach: Process caracterizationProcess performance qualification
Anne_Carpenter photo (003).jpg
  • assayGene clusterbased on morphological similarity: Express each gene, gene painting Image analysis, cluster morphological profiles
  • identification of allelle that are not constitutively activating mutants.
  • weakly supervised deep learning to extract features
  • identify similarities and differences among treatments at the same population level
  • Predict many distinct expensive assays on a huge compound library using a single cell painting
  1. Test 5,000 compounds in the assay of interest as well as cell painting
  2. Find combination of iamge-based features that predict in the assay of interest
  3. Predict “hit” from existing 1Million compound cell paining data set
The Role of AI in Expediting Drug Discovery Target Identification for Nonalcoholic Steatohepatitis Using Machine Learning: The Case for nference
Tyler Wagner PhD, Head of Cardiovascular Research, nference
KJ.jpg
DT.jpg
  • Lung-Chip Applications
  • Pulmonary inflammation
  • Intestine-chip Applications
  • Liver-Chip: Building Tissue Complexity: Co-culture, tri-culture, quatro-culture, Transcriptomic Analysis
  • Liver-Chip: Kupffer cells Characterization
  • Stellate Cells
  • parenchymal channel, non-parenchymal channel
  • Liver Chip: Predicting species differences in liver toxicity: Effects of Bosentan on Albumin secretion
  • Acetaminophen Toxicity in Liver-Chip: APAP Metabolism: detected changes in morphology, ATP, GSH – Dosepdependent increase of ROS
  • Steatosis and Stellate Cell Activation: and Species difference in Toxicity Liver chip data correlates with in vivo data
  • Predict Human safety risks with liver chip
Albert Gough, PhD, U Pittsburg School of Medicine
  • Approaches for repurposing drugs:
  1. Integrated, fluidic organ MPD,
  2. cells, 3D structures,
  3. O2 Modulation & Sensing
  4. Biosensors
  5. secretome
  • Higher Biomimetic content Higher throughput
  • regulatory liver-pancreas axis in Type 2 Diabetes model
  • Estradiol-Induced proliferation of mutants in Breast Cancer varies from 2D monoculture to 3D LAMP
  • MPS Models:
  1. celle and organ Structure in MPS
  2. Single organ MPS & Coupled organ
Carey Goldberg.PNG
Carey Goldberg, WBUR
burke family.jpg

September 24, 2019

jim.jpg
david hysong.png
bill siders.png
eric green.jpg
MacArthurD.jpg
mackay_1644931c.jpg
timothy yu.jpg
fernando-vieira.jpg
crop-VOISCHTS-Presenter-ZimmermannM.png
Allyson-Berent.jpg

Read Full Post »

Older Posts »